WHIM syndrome is a rare autosomal dominant immunodeficiency disorder which results in multiple mutations that remove 10-19 amino acids from the carboxy-terminus of CXCR4, a chemokine receptor expressed by both hematopoietic and non-hematopoietic cells [Hernandez 2003]. The mutation in the CXCR4 receptor is known to prevent the normal release of mature neutrophils from the bone marrow to the blood [Kawai 2005] resulting in neutropenia in patients with WHIM syndrome [Dale 2011]. In addition to neutropenia, WHIM syndrome is characterized by lymphopenia that affects the levels of circulating T and B cells. [Balabanian 2012, Dotta 2011] resulting in low levels of immunoglobulins. The exact mechanism for lymphopenia is not known but may be attributable to interruption of the normal trafficking of lymphocytes and their retention in the marrow and other lymphoid tissues [Ma 1999].
Generally, clinical symptoms first appear in early childhood with recurrent bacterial infections due to low levels of white blood cells and antibodies [NORD 2015]. Common infections include otitis media, cellulitis, impetigo, abscess, bacterial pneumonia, sinusitis, and periodontitis. Affected individuals are particularly susceptible to human papillomavirus (HPV), which can cause widespread warts affecting the hands, feet, face, and trunk and are often recalcitrant [NORD 2015]. Mucosal and genital warts may also develop and these warts are associated with an increased risk of progressing to cervical carcinoma [NORD 2015]. Current treatments include G-CSF and intravenous immunoglobulin but these are non-specific, expensive, difficult to administer, and only partially effective [Kawai 2009].
Present treatments available for patients with WHIM syndrome are insufficient. There is a clear unmet need for agents that improve outcomes in the treatment of such patients.